The Manipulator tends to have roots that go right back to the hero's origin and before. That's why movie retcons have but Osborn indutries experiements behind Parker's radioactive spider, why the Joker killed Batman's parents etc.

The Manipulator is often behind the scenes, pulling the strings, and so tends to touch those parts of the hero's life that elicit dramatic emotional response. In Iron Man's case, the Manipulator doesn't usually seek to kill Iron Man, he wants to take away Stark Industrries, Tony's life work. In Spidey's case with Osborn it's the triumph of power over responsibility as a corporate businessman abuses his position and resources (but yeah, he's only become a Manipulator in his more recent post-death retcon appearances). The Kingpin gives a face to the inexorable grip of organised crime. Immortus interferes with the whole life-direction of heroes for his own twisted ends.